USPTO Patents Application 10687850

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organizatio

International Bureau

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

(43) International Publication Date (10) International Publication Number

6 March 2003 (06.03.2003) PCT WO 03/019166 Al

(51) International Patent Classification 7 :

// 33/49, A61B 5/053

G01N 27/02 (74) Agent: DR LUDWIG BRANN PATENTBYRA AB;

(Drottninggatan 7), Box 1344, S-75143 Uppsala (SB).

(21) International Application Number: PCT/SE02/01530

(22) International Filing Date: 27 August 2002 (27.08.2002)

(25) Filing Language: English

(26) Publication Language: English

(30) Priority Data:

0102896-8 29 August 2001 (29.08.2001) SE

(71) Applicant (for all designated States except US): HAEMO
WAVE AB [SE/SE]; Box 840, S-98228 Gallivare (SE).

; (72) Inventors; and

j (75) Inventors/Applicants (for US only): KASTEBO, Ove

! [SE/SE]; Hedparken 17, S-98235 Gallivare (SE). KOIT-

j SALU, Evald [SE/SE] ; SKansbergsvagen 27, S-14170

j Huddingc (SE). NILSSON, Bertil [SE/SE]; Karabyvaacn

! 285, S-24471 Dosjebro (SE).

(81) Designated States (national): AE, AG, AL, AM, AT (util-
ity model), AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA,
CH, CN, CO, CR, CU, CZ (utility model), CZ, DE (util-
ity model), DE, DK (utility model), DK, DM, DZ, EC, EE
(utility model), EE, ES, FI (utility model), FI, GB, GD, GE,
GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ,
LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN,
MW, MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD,
SE, SG, SI, SK (utility model), SK, SL, TJ, TM, TN, TR,
TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW.

(84) Designated States (regional): ARIPO patent (GH, GM,
KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
Eurasian patent (AM. AZ. BY, KG, KZ, MD, RU, TJ, 'I'M),
European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, SK,
TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
GW, ML, MR, NE, SN, TD, TG).

Published:

wiih international search report

[Continued on next page]

: (54) Title: SYSTEM AND METHt )D F( )R BLOOD ANALYSIS

(57) Abstract: A method for blood analysis, comprising detecting the imaginary part of the complex impedance in a blood sam-
pie having an unknown haemoglobin concentration, and directly correlating the imaginary part of the complex impedance with the
haemoglobin concentration in said blood sample.

WO 03/019166 Al llllllllllllllllllllllllllllllllllllllllllllllllll

For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations " a/ >pearing al the begin-
ning of each regular issue of the PCT Gazette.

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1

SYSTEM AND METHOD FOR BLOOD ANALYSIS

The Field of the Invention

5 The present invention relates to a system and a method for measuring the

haemoglobin value in blood, more specifically to measurements in a closed system.

Background of the Invention

10 Today's techniques for measuring the haemoglobin value in blood often lead to

variations in the results of measurement since the analyses are performed on very
small blood volumes (approx. 5-20 jul) , and therefore the operator's sampling
technique is important for the results of the measurement.

15 Furthermore, these known methods often involve a health risk for the operator, due
to exposure to chemicals and contagious blood.

The conventional methods also involve high costs for disposable material and for
handling waste of disposable material and chemicals.

20

Hematocrit values obtained by conventional analyses can most of the time be
correlated to the haemoglobin value, but they fail when measuring blood from
patients suffering from certain blood anomalies which may cause the blood to
contain abnormally large or small blood cells.

25

Methods for measuring hematocrit values are sometimes used when determining a
state of anaemia and are much simpler than a method for measuring the oxygen-
carrying component, haemoglobin, directly (see US-4 547 735, EP-0 417 796 and
JP-03 099 254).

30

The above prior arts methods involve measuring the impedance in blood.

35

Traditional techniques for measuring the hematocrit value involve measuring the
packed cell mass in a sample tube containing a blood sample. This measurement is
performed after the blood sample having been centrifuged.

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2

In Ackmann et al, Specific impedance of canine blood, Ann. Biomed. Eng., 24 (1), 58
(1996), measurements are disclosed where the imaginary part of the complex
impedance is correlated with hematocrit value. Frequency intervals of 5 kHz to 1
5 MHz have been used when analysing canine blood. This measuring technique
involves non-direct measurement of the haemoglobin value.

WO/ 0009996 or its equivalent US-5 792 668 discloses specific determination of
glucose in NaCl using a radio frequency spectral analysis method. This method
1 0 comprises analysing the real and the imaginary part of the complex impedance in
the radio frequency range up to 5 GHz.

Summary of the Invention

15 Thus, there is a great need for a method for directly measuring the haemoglobin

value in blood which does not pose a health risk to the user, does not involve high
costs for handling of the disposable material used and enables measurements of
small volumes of blood with accuracy.

20 In view of the drawbacks associated with prior art methods it is therefore the object
of the present invention to provide a system and a method that yields accurate
haemoglobin results for small blood samples. This object is achieved with a method
according to claim 1 and a system according to claim 9.

25 The inventors have developed a technique primarily for determining the

haemoglobin value in human blood in a closed system. Thus, the present invention
permits safe measurements of the haemoglobin value in blood, eliminating the
user's exposure to chemicals and contagious blood.

30 The present invention also provides a system that presents high reliability in

measurement results and that comprises a procedure of analysis that is so simple
that only minimal laboratory experience is needed.

Furthermore, the present invention rmnimises the production of environmentally
35 detrimental waste like plastics and chemicals.

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The aim of the invention is also to provide a method that does not involve addition
of agents that degrade the blood samples, so that an analysed blood sample can be
used for further analyses at for example a central laboratory.

5

Brief description of the drawings

The present invention will now become more fully understood from the detailed
description given herein, wherein reference is made to the accompanying drawings,
10 in which,

Fig. 1 shows a scheme over the haemoglobin measuring system according to the
present invention.

1 5 Fig. 2 shows a calibration curve that illustrates the measured reference

haemoglobin values as a function of its corresponding imaginary part of the
complex impedance (values deriving from measurements performed at 400 kHz) .

Fig. 3 shows a graph correlating the measured reference haemoglobin values and
20 the haemoglobin values calculated using the inventive method (values originating
from measurements of the imaginary part of the complex impedance performed at
400 kHz).

Fig. 4 shows a calibration curve, which shows the measured reference haemoglobin
25 values as a function of its corresponding imaginaiy part of the complex impedance
(values deriving from measurements performed at 500 kHz).

Fig. 5 shows a graph correlating the measured reference haemoglobin values and
the haemoglobin values calculated using the inventive method (values originating
30 from measurements of the imaginary part of the complex impedance performed at
500 kHz).

Fig. 6 shows a calibration curve, which shows the measured reference haemoglobin
values as a function of its corresponding imaginary part of the complex impedance
35 (values deriving from measurements performed at 600 kHz).

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Fig. 7 shows a graph correlating the measured reference haemoglobin values and
the haemoglobin values calculated using the inventive method (values originating
from measurements of the imaginary part of the complex impedance performed at
5 600 kHz).

Fig. 8 shows a calibration curve, which shows the measured reference haemoglobin
values as a function of its corresponding imaginary part of the complex impedance
(values deriving from measurements performed at 700 kHz) .

10

Fig. 9 shows a graph correlating the measured reference haemoglobin values and
the haemoglobin values calculated using the inventive method (values originating
from measurements of the imaginary part of the complex impedance performed at
700 kHz).

15

Fig. 10 shows a calibration curve, which shows the measured reference
haemoglobin values as a function of its corresponding imaginary part of the
complex impedance (values deriving from measurements performed at 800 kHz).

20 Fig. 1 1 shows a graph correlating the measured reference haemoglobin values and
the haemoglobin values calculated using the inventive method (values originating
from measurements of the imaginary part of the complex impedance performed at
800 kHz).

25 Fig. 12 shows a calibration curve, which shows the measured reference

haemoglobin values as a function of its corresponding imaginary part of the
complex impedance (values deriving from measurements performed at 900 kHz) .

Fig. 13 shows a graph correlating the measured reference haemoglobin values and
30 the haemoglobin values calculated using the inventive method (values originating
from measurements of the imaginary part of the complex impedance performed at
900 kHz).

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Detailed Description of the Invention

When directly measuring the haemoglobin value in the blood sample according to
the present invention, one uses the fact that the blood has an alternating current
5 (A.C.) impedance constituted by a resistive and a reactive part, where the reactive
part is constituted by the imaginary part of the complex impedance.

The above-mentioned prior art hematocrit measurements differ from the method
according to the present invention in that they do not analyse the resistive and/ or
10 the reactive part separately.

If a molecule is exposed to an alternating electrical field, e.g. between two electrodes
constituting a capacitor, it is influenced such that a capacity change occurs.

15 The reactive part of the alternating current impedance of the blood is dependant on
the amount of haemoglobin in the blood sample. The electrical complex impedance
of the blood sample can then be measured and the magnitude of the reactive part,
i.e. the imaginary part of the complex impedance, can be correlated with the
haemoglobin value in the blood.

20

In the measurements according to the above-mentioned publication by Ackmann
the imaginary part of the complex impedance is correlated with hematocrit value
and not haemoglobin value, i.e. haemoglobin is not measured directly. Ackmann
uses frequency intervals of 5 kHz to 1 MHz when analysing canine blood.

25

The present inventors have now identified frequency ranges where correlation
between the haemoglobin value and the imaginary part of the complex impedance
exists at least over a certain range in Hb concentration.

30 The results described herein have been obtained by exciting haemoglobin molecules
in blood samples by applying an alternating field within a range of 400-900 kHz on
the blood sample using two electrodes. This frequency range partly overlaps the
frequency range that Ackmann uses.

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There are thus several differences between this method and the method according
to the present invention.

The system according to the present invention will be described with reference to
Fig. 1, in which it is generally described with 1. The system includes electrodes 204,
5 an impedance meter 205, a display unit 210, a keyboard 211 and a memory
(RAM/ROM) 212.

The impedance meter 205 comprises a signal generator 206 and a signal-processing
unit 207. The signal generator is capable of delivering an alternating current in a
10 frequency range of 50 - 1200 kHz and measuring the impedance at one or more
frequencies within the frequency range 50 - 1200. kHz. The signal-processing unit
207 delivers an out-signal in analogue or digital form.

In Fig. 1 there is also shown a sample tube 202 containing a blood sample 203. A
15 septum, a rubber cork or the like seals the tube.

To obtain the raw data from said blood sample, a network analyser (Rohde 8b
Schwarz ZVC) including some additional equipment belonging to it and a measuring
device was used. In the development work at The Technical University of Lulea. the
20 vector network analyser that was used contained a signal generator 206 and a
signal-processing unit 207 (see Fig. 1).

The electrodes are preferably made of a material that does not oxidise, has good
conductivity and does not affect the blood sample, e.g. platinum.
25 Said electrodes are arranged in a tightly sealed tube, preferably in an ordinary
sample tube.

The system according to the invention uses only two electrodes 204, a measuring
electrode and a reference electrode, but any number of electrodes can be employed
30 in combination.

To prevent air bubbles from interfering with the measuring process, the electrodes
204 of the measuring device are introduced from below into the sealed blood sample
tube 202 mounted upside-down, so that the electrodes penetrate the sealing of the

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blood sample tube and come into direct contact with the blood without first passing
through air.

The signal generator 206 generates the electrical alternating field, which is applied
5 to the blood sample 203 via the electrodes 204, the electrical alternating field
preferably having a frequency within the range 50 - 1200 kHz.

The signal from the electrodes is amplified and filtered by the signal-processing unit
207, as a preparation for the transformation from analogue to digital form.

10

After filtering and amplification the signal-processing unit 207 processes the signal
mathematically, whereby the reactive part of the signal is correlated with the
haemoglobin value of the blood. This is performed within the frequency range 50 -
1200 kHz, and preferably at about 800 kHz, since the best correlation has been
15 obtained at this frequency.

This information is subsequently prepared for presentation on the display unit 210.
From the keyboard 211a user can interact with the system, such as feeding it with
patient information and data, in addition to controlling the system.

20

Furthermore, the signal-processing unit 207 is coupled to a memory 212, which
preferably comprises a RAM and a ROM, wherein measurement data and other
information can be saved and read.

25 The method according to the present invention is based on the discovery that within
certain frequency intervals correlation exists between the haemoglobin value in
blood within a certain concentration range and its imaginary part of the complex
impedance.

30 In order to perform the method according to the invention, a standard curve must
be constructed. The imaginary part of the complex impedance is then measured
and correlated with the haemoglobin value using the standard curve.

The standard curve is constructed by first centrifuging a reference blood (arbitrary
35 blood sample) to obtain plasma. The plasma is then used to dilute the reference

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blood to five appropriate concentrations in haemoglobin. These concentrations lie in
the range of normal human haemoglobin values. This interval is chosen because it
matches the interval in which the ordinary measurement will be performed, but it is
also chosen because linearity exists in this interval, at least for haemoglobin values
5 of 80 to 180.

The haemoglobin values in these samples are then measured with a reference
instrument.

10 The respective corresponding imaginary parts of the complex impedance are

determined at a frequency within the frequency range 50 - 1200 kHz using the
above-mentioned network analyser (Rohde & Schwarz ZVC) .

The impedance results, obtained at the chosen frequency, are correlated with the
1 5 haemoglobin results obtained with the reference instrument. The equation of a

calibration curve within the above-mentioned range is determined. A ready-to-use
system comprises a computer system having one or more of these equations stored
in its memory unit. When performing the haemoglobin measurements the computer
will then perform the correlation procedure.

20

The measurement of the imaginary part of the complex impedance in patient blood
samples is performed by analysing blood samples from patients using the above-
described measuring equipment (Rohde & Schwarz ZVC) at the same frequency
within the frequency range 50 - 1200 kHz as mentioned above.

25

The results obtained from measuring the imaginary part of the complex impedance
at the chosen frequency are fed into the equations of the respective calibration
curve, yielding calculated corresponding haemoglobin values.

30 The reproducibility of the described method was determined by analysing several
times each of a number of patient samples with the measuring equipment. The
variation expressed in %CV was 2,5 or lower at the level 80 - 135 g haemoglobin/1.

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Examples

The method will now be described with reference to non-limiting examples.
5 Example 1 . Correlation studies of haemoglobin at 400 kHz
Construction of a standard curve

A reference blood sample (normal sample) was centrifuged and the plasma was
10 separated in order to be used for dilution of the blood sample to 5 different levels of
haemoglobin.

The diluted samples were analysed with a reference instrument (SYSMEX SF-3000)
at the levels 65, 85, 141, 151 and 179 g/1 considering the haemoglobin values.

15

An alternative way would be to provide a reference blood sample exhibiting a known
haemoglobin concentration and then dilute said reference blood sample to obtain a
set of reference samples having different known haemoglobin concentrations.

20 Still another way would be to provide a plurality of reference blood samples
exhibiting unknown haemoglobin concentrations and then determine the
haemoglobin concentrations in said reference blood samples to obtain a set of
reference samples having different known haemoglobin concentrations.

25 The corresponding imaginary part of the complex impedance for each sample was
determined at 400 kHz using the above-mentioned network analyser (Rohde &
Schwarz ZVC).

The impedance results obtained at 400 kHz were correlated with the haemoglobin
30 results obtained with the reference instrument. The equation of a calibration curve
within the mentioned range (65 - 179 g/1) was determined (see Fig. 2).

The standard curve shows the haemoglobin values (Hb) of the above-mentioned
blood samples, as obtained with the reference instrument, as a function of their
35 corresponding imaginary parts of the complex impedance.

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The obtained values were correlated and the following equation was drawn up:
Y = A + B*X

5 where Y represents the haemoglobin values in the reference blood sample and X
their corresponding imaginary parts of the complex impedance.

The factor A and the coefficient B were found to be 32,62 and -1632, respectively.

10 The R and the R-square values were 0.9955 and 0,9910, respectively (see Fig. 2).

Measurement of a patient sample

Subsequent to the construction of the standard curve 93 patient blood samples
15 were analysed using both the reference instrument and the above-described
measuring equipment at 400 kHz.

The results obtained from measuring the imaginary part of the complex impedance
were fed into the previously made calibration curve to transform them to
20 haemoglobin values.

The calculated haemoglobin values (X- values), ranging between 80-180 were
correlated with the haemoglobin values from the reference instrument (Y- values) .

25 It was found that the factor A and the coefficient B were 12,33 and 0,7868,
respectively.

The R and the R-square values were 0.8563 and 0,7333, respectively (see Fig. 3).

30 Example 2. Correlation studies of haemoglobin at 500 kHz

The standard curve for the measurement performed at 500 kHz was constructed in
the same manner as in Example 1, which for this frequency resulted in A and B
being 31,60 and -1451, respectively, and R and R-square being 0,9966 and 0,9932,
35 respectively (see Fig. 4).

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The correlation studies, which also were performed in the same manner as in
Example 1, resulted in A and B being 6,065 and 0,8441, respectively, and R and R-
square being 0,8943 and 0,7998, respectively (see Fig. 5).

5

Example 3. Correlation studies of haemoglobin at 600 kHz

The standard curve for the measurement performed at 600 kHz was constructed in
the same manner as in Example 1, which for this frequency resulted in A and B
10 being 30,67 and -1336, respectively, and R and R-square being 0,9974 and 0,9949,
respectively (see Fig. 6).

The correlation studies, which also were performed in the same manner as in
Example 1, resulted in A and B being 6,119 and 0,8578, respectively, and R and R-
15 square being 0,9030 and 0,8155, respectively (see Fig. 7).

Example 4. Correlation studies of haemoglobin at 700 kHz

The standard curve for the measurement performed at 700 kHz was constructed in
20 the same manner as in Example 1, which for this frequency resulted in A and B

being 29,88 and -1255, respectively, and R and R-square being 0,9981 and 0,9961,
respectively (see Fig. 8).

The correlation studies, which also were performed in the same manner as in
25 Example 1, resulted in A and B being -0,7240 and 0,9136, respectively, and R and
R-square being 0,9453 and 0,8937, respectively (see Fig. 9).

Example 5. Correlation studies of haemoglobin at 800 kHz

30 The standard curve for the measurement performed at 800 kHz was constructed in
the same manner as in Example 1, which for this frequency resulted in A and B
being 29,42 and -1200, respectively, and R and R-square being 0,9984 and 0,9968,
respectively (see Fig. 10).

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The correlation studies, which also were performed in the same manner as in
Example 1, resulted in A and B being -1,120 and 0,9088, respectively, and R and R-
square being 0,9478 and 0,8983, respectively (see Fig. 11).

5 Example 6. Correlation studies of haemoglobin at 900 kHz

The standard curve for the measurement performed at 900 kHz was constructed in
the same manner as in Example 1 , which for this frequency resulted in A and B
being 29,13 and -1 155, respectively, and R and R-square being 0,9986 and 0,9971,
10 respectively (see Fig. 12).

The correlation studies, which also were performed in the same manner as in
Example 1, resulted in A and B being 3,189 and 0,9021, respectively, and R and R-
square being 0,9470 and 0,8967, respectively (see Fig. 13).

15

It should be understood that the detailed description and specific examples, while
indicating preferred embodiments of the invention are given by way of example only.
Various changes and modifications within the spirit and scope of the invention will
become apparent to those skilled in the art from this detailed description.

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A method for blood analysis, comprising

detecting the imaginary part of the complex impedance in a blood sample
having an unknown haemoglobin concentration, and

directly correlating the imaginary part of the complex impedance with the
haemoglobin concentration in said blood sample.

Method for blood analysis according to claim 1 , wherein the imaginary part
of the complex impedance is measured within the frequency range 50-1200
kHz, preferably at about 800 kHz.

Method for blood analysis according to claim 2, wherein the imaginary part
of the complex impedance is measured at one or more frequencies within
said frequency range.

Method for blood analysis according to any of claims 1-3, which prior to the
step of detecting the imaginary part of the complex impedance, comprises the
further steps of:

providing a reference blood sample exhibiting an unknown haemoglobin
concentration;

diluting said blood reference sample to obtain a set of reference blood
samples having unknown haemoglobin concentrations;

determining the haemoglobin concentrations in said reference blood samples
to obtain a set of reference blood samples having known haemoglobin
concentrations ;

35

applying an alternating current (A.C.) electrical field to each reference blood
sample using electrodes in direct contact with the blood,

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measuring the imaginary part of the complex impedance of each of said
reference blood sample, at one or more frequencies within the frequency
range 50 - 1200 kHz,

correlating the imaginary part of the complex impedance with the
haemoglobin value of the blood in each of said reference samples to obtain
one or more standard curves.

Method for blood analysis according to any of claims 1-3, which prior to the step of
detecting the imaginary part of the complex impedance, comprises the further steps of:

providing a plurality of reference blood samples exhibiting unknown
haemoglobin concentrations;

determining the haemoglobin concentrations in said reference blood samples
to obtain a set of reference samples having different known haemoglobin
concentrations;

applying an alternating current (A.C.) electrical field to each reference blood
sample using electrodes in direct contact with the blood,

measuring the imaginary part of the complex impedance of each of said
reference blood sample, at one or more frequencies within the frequency
range 50 - 1200 kHz,

correlating the imaginary part of the complex impedance with the
haemoglobin value of the blood in each of said reference samples to obtain
one or more standard curves.

Method for blood analysis according to any of claims 1-3, which prior to the
step of detecting the imaginary part of the complex impedance, comprises the
further steps of:

35

providing a reference blood sample exhibiting a known haemoglobin
concentration;

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15

diluting said reference blood sample to obtain a set of reference samples
having different known haemoglobin concentrations;

5 applying an alternating current (A.C.) electrical field to each reference blood

sample using electrodes in direct contact with the blood,

measuring the imaginary part of the complex impedance of each of said
reference blood sample, at one or more frequencies within the frequency
10 range 50 - 1200 kHz,

correlating the imaginary part of the complex impedance with the
haemoglobin value of the blood in each of said reference samples to obtain
one or more standard curves.

15

7. Method for blood analysis according to any of claims 4-6, whereby the
correlation comprises feeding the result obtained from measuring the
imaginary part of the complex impedance of a blood sample having an
unknown haemoglobin concentration at the chosen frequency/ frequencies

20 into said calibration curve /curves, to obtain its corresponding calculated

haemoglobin concentration based on the imaginary part of the complex
impedance of said blood sample.

8. Method for blood analysis according to claim 1, comprising

25

measuring the impedance in a blood sample having an unknown
haemoglobin concentration using an impedance meter at one or more
frequencies within the frequency range 50 - 1200 kHz.

30 9. A system for blood analysis, comprising

at least two electrodes (204) adapted to be introduced into a blood sample
(203);

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an impedance meter (205) coupled to said electrodes (204) and capable of
delivering an alternating current in a frequency range of 50 - 1200 kHz, so as
to enable measurement of impedance at one or more frequencies within said
frequency range, and to deliver an out-signal in analogue or digital form;

a signal processing unit (207) for processing the impedance signal and
calculating a haemoglobin value on the basis of said measured impedance.

o O o

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1/7

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4/7

■ • Data -t-Y = 30,6693- 1335, 53'Xj

;— 95% Confidence (Data) — «— 95% Confidence (Line) I

2CO--

• 'it.;.-:.- :

180-

160-

140-

120-

100-

80

60-

40-

20-

-0,12 -0,1 -0,08 -0,06 -0,04 -0,02 0

Im j

i

Fig. 6

| * Data --7— Y = 6,1 1897+ 0,85777*X

j — «— 95% Confidence (Data) —a— 95% Confidence (Line)

"4 - ^

80 100 120 140 160 180 200

Fig. 7

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Fig. 9

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6/7

• Data — ▼ — Y = 29,41 53- 1 200,29*X
95% Confidence (Data) — «— 95% Confidence (Line)

5^ .

24 0-

-190-

-1-70--

•

-150-

-130-

-140-

90-

70-

50-

-0,14 -0,12 -0,1 -0,08 -0,06 -0,04 -0,02

Fig. 10

j • Data -r—Y= 1,11953 + O,90875*X

j — ♦- 95% Confidence (Data) - a - 95% Confidence (Line)

200 i :

80 100 120 140 160 180 200

Calc. Hb

Fig. 11

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Fig. 13

INTERNATIONAL SEARCH REPORT

I Interna

I PCT/i

I Internatcoiial application No.

PCT/SE 02/01530

A. CLASSIFICATION OF SUBJECT MATTER

IPC7: G01N 27/02 // G01N 33/49, A61B 5/053

According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED

Minimum documentation searched (classification system followed by classification symbols)

IPC7: G01N

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

SE,DK,FI,N0 classes as above

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

WPI DATA, EPQ INTERNAL, PAJ, MEDLINE, CAPLUS, INSPEC, BIOSIS, EMBASE, SCISE
ARCH

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

EP 0417796 A2 (KABUSHIKI KAISHA TOYOTA CHUO
KENKYUSHO) , 20 March 1991 (20.03.91),
abstract

Med. Biol. Eng. Comput. vol. 37, 1999,

M.Y. Jaffrin et al : "Comparison of optical,
electrical, and centr if ligation techniques
for haematocrit monitoring of dlalysed
patients", pages 433-439, abstract

| | Further documents are listed in the continuation of Box C. | yj See patent family a

Special categories of cited

it defining the general

te of ft

be of particular relevance
"E" earlier application or patent but published on or after the international
filing date

"L" document which may throw doubts on priority claims) or which is
cited to establish the publication date of another citation or other
special reason (as specified)

"O" document referring to an oral disclosure, use, exhibition or other

al filing date but later than

"T" later document published after the international filing date or priority
date and not in conflict with the application but cited to understand
the principle or theory underlying the invention

"X" document of particular relevance: the claimed invention cannot be
considered novel or cannot be considered to involve an inventive
step when the document is taken alone

" Y" document of particular relevance: the claimed invention cannot be
considered to involve an inventive step whe- - ' -

being obvious to a person skilled in the art
ber of the same patent family

Date of the actual completion of the international search

3 December 2002

Date of mailing of the international search report

0 4-12- 2002

Name and mailing address of the ISA/
Swedish Patent Office
Box 5055, S-102 42 STOCKHOLM
Facsimile No. + 46 8 666 02 86

Authorized officer

Jens Waltin/Els

Telephone No. +46 8 782 25 00

Form PCT/ISA/210 (second sheet) (July 1998)

INTERNATIONAL SEARCH REPORT

Information on patent family n

InternasTBnal application No.

PCT/SE 02/01530

0417796 A2 20/03/91

SE 0417796 T3

DE 69014262 D,T 20/07/95

JP 2665806 B 22/10/97

JP 3099254 A 24/04/91

Form PCT/ISA/210 (patent family annex) (July 1998)

DERWENT-ACC-NO: 2003-300754

DERWENT— ACC— NO : 2003-300754
DERWENT— WEEK : 20 0452

COPYRIGHT 2008 DERWENT INFORMATION LTD

TITLE: Blood analysis for measuring hemoglobin

value, involves detecting imaginary part
of complex impedance in blood sample
having unknown hemoglobin concentration,
and directly correlating imaginary part
with hemoglobin concentration

INVENTOR: KASTEBO, 0; KOITSALU, E ; NILSSON, B

PATENT-ASSIGNEE: HAEMO WAVE AB [HAEMN]

PRIORITY-DATA: 2001SE-0002896 (August 29, 2001)

PATENT-FAMILY :

PUB-NO PUB— DATE LANGUAGE PAGES MAIN-IPC

AU 2002327988 Al March 10, N/A 000 G01N 027/02

2003

WO 2003019166 Al March 6, E 027 G01N 027/02
2003

SE 200102896 A March 1, N/A 000 G01N 027/02
2003

SE 521208 C2 October 14, N/A 000 G01N 027/02
2003

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DERWENT-ACC-NO: 2003-300754

DESIGNATED— STATES :

AE AG AL AM AT AU AZ BA BB BG BR BY BZ

CA CH CN CO CR CU CZ DE DK DM DZ EC EE

ES FI GB GD GE GH GM HR HU ID IL IN IS

JP KE KG KP KR KZ LC LK LR LS LT LU LV

MA MD MG MK MN MW MX MZ NO NZ OM PH PL

PT RO RU SD SE S G SI SK SL TJ TM TN TR

TT TZ UA UG US UZ VC VN YU ZA ZM ZW AT

BE BG CH CY CZ DE DK EA EE ES FI FR GB

GH GM GR IE IT KE LS LU MC MW MZ NL OA

PT SD SE SK SL SZ TR TZ UG ZM ZW

APPLICATION-DATA :

APPL-DESCRIPTOR APPL-NO

AU2002327988A1 N/A

AU2002327988A1 Based on
WO2003019166A1 N/A

SE 200102896A N/A

SE 521208C2

N/A

APPL-
DATE

2002AU-0327988 August

27, 2002
WO2003019166 N/A
2002WO-SE01530 August

27, 2002
2001SE-0002896 August

29, 2001
2001SE-0002896 August

29, 2001

INT-CL (IPC) : A61B005/053, G01N027/02 , G01N033/49

ABSTRACTED-PUB-NO: WO 200301916 6A

BASIC-ABSTRACT:

NOVELTY - Analysis of blood, includes:

(1) detecting the imaginary part of complex impedance in a
blood sample having unknown hemoglobin concentration; and

(2) directly correlating the imaginary part of complex
impedance with the hemoglobin concentration.

DETAILED DESCRIPTION - An INDEPENDENT CLAIM is also

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DERWENT-ACC-NO: 2003-300754

included for a blood analysis system comprising:

(1) at least two electrodes (204) for introduction into a
blood sample (203) ;

(2) an impedance meter (205) coupled to the electrodes and
capable of delivering an alternating current at 50 - 1200
kHz to allow measurement of impedance at more than one
freguencies within the range and to deliver an out-signal
in analog or digital form; and

(3) a signal processing unit (207) for processing the
impedance signal and calculating hemoglobin value based on
the measured impedance .

USE - Analysis is used for measuring the hemoglobin value
in blood sample.

ADVANTAGE - The analysis permits safe measurements of
hemoglobin value in blood, eliminating the user's exposure
to chemicals and contagious blood. It does not involve high
costs for handling of disposable material used, and enables
measurement of small blood volume with accuracy.

DESCRIPTION OF DRAWING (S) - The figure is a schematic view
of a blood analysis system.

Blood sample 203

Electrodes 204

Impedance meter 205

Signal processing unit 207

CHOSEN— DRAWING : Dwg .1/13

TITLE-TERMS: BLOOD ANALYSE MEASURE HAEMOGLOBIN VALUE

DETECT IMAGINARY PART COMPLEX IMPEDANCE
BLOOD SAMPLE UNKNOWN HAEMOGLOBIN
CONCENTRATE CORRELATE IMAGINARY PART
HAEMOGLOBIN CONCENTRATE

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DERWENT-ACC-NO: 2003-300754

DERWENT— CLASS : B04 P31 S03

CPI-CODES:

EPI-CODES:
CHEMICAL-CODES :

B04-B04D2; B04-B04D5; B11-C08D; B11-C09;
B12-K04A;

S03-E02; S03-E14H; S03-E14H1;
Chemical Indexing Ml *01*
Code M417 M423 M750 M905
Compounds A04LJK A04LJA

Fragmentation
N102 Specfic

Chemical Indexing M6 *02* Fragmentation
Code M905 R501 R515 R528 R611 R637

SECONDARY-ACC-NO :

CPI Secondary Accession Numbers: C2003-078443
Non-CPI Secondary Accession Numbers : N2003-239242

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